The intent of the proposed research is to follow prospectively all available SCID infants born in the United States and Canada to evaluate systematically for the first time factors influencing the outcomes of the multiple forms of hematopoietic cell therapy (HCT) for SCID currently being employed. This study will use state of the art methods to define the molecular genotypes and characterize serially multiple key parameters of immunological reconstitution. Aim 1) To determine the effects patient-related factors have on survival, time course of immune reconstitution and clinical outcome of HCT for SCID, including age at transplantation, presence of viral infections, lymphocyte phenotype, molecular genotype and the presence of transplacentally transferred maternal lymphocytes. Aim 2) To determine the effects adequacy of HLA matching of donor and recipient have on survival, the time course of immune reconstitution and clinical outcome of HCT for SCID. For the majority of patients who must receive HLA-mismatched transplants, source of donor cells (haploidentical mother vs. father, HLA-matched unrelated adult or cord blood), methods of T cell depletion or CD34 cell selection, and cell numbers given (both CD34+ stem cells and CD3+ T cells) will be comparatively examined, with particular focus on the occurrence, severity and duration of GVHD and ultimate multilineage engraftment. Aim 3) To determine the effects the use (or not) and type of pre-transplant conditioning have on survival and on the immunologic and clinical outcomes of HCT. This project will help accomplish the proposal's overall objective of improving definitive therapy for SCID by comparing relatively short term outcomes of the different treatments currently being employed for HCT in SCID in a temporally homogeneous cohort of patients under defined patient and donor circumstances. It will define early biomarkers that predict survival, the earliest immune reconstitution or lack of it, and the risk for chronic GVHD and/or autoimmune disease. It can be anticipated that the results of this prospective study will help design clinical trials aiming at defining strategies to optimize survival, long-term immune reconstitution and to reduce complications after HCT for SCID.